Endogenous mechanisms of ischemic preconditioning-tolerance have reviled the brain's ability to reprogram (precondition) its response to acute ischemia from that of induced cell injury signaling cascades to induction of neuroprotective pathways (tolerance). Such endogenous neuroprotection occurs through Toll Like Receptor (TLR) signaling which reprograms an inflammatory (injurious) response to stroke into an anti- inflammatory (neuroprotective) response. We offer the preferred agonists (CpG ODNs and imiquimod - IMQ) of TLR 9 and 7 respectively as lead compounds for prophylactic neuroprotection against stroke. Although robust rodent data have been produced, past and recent translational failures require additional preclinical evaluation. Accordingly, we have developed a new primate stroke model for assessment of putative pharmacotherapeutics and propose to perform rigorous trials of our recently discovered neuroprotectants to establish essential efficacy and pharmacokinetic data. Thus our preliminary studies support new robust neuroprotective strategies for high-risk stroke patients to be further tested in the non-human primate via: Aim 1. Determine the optimal dose to achieve neuroprotective efficacy for TLR9 (K- and D-mix CpG ODNs) and TLR7 (IMQ) candidate drugs as prophylactic therapy in a NHP model of cortical stroke. Aim 2. Determine the time window of neuroprotective efficacy for K- and D-mix CpG ODNs and IMQ as prophylactic therapy in a NHP model of cortical stroke. Aim 3. Determine neuroprotective efficacy CpG ODN (K and D mix) and IMQ as prophylactic therapy in a model of cortical stroke in the aged NHP. Aim 4. Determine the neuroprotective efficacy of repeated administration of CpG ODN (K- and D-mix) and IMQ as prophylactic therapy in a NHP model of cortical stroke. Aim 5. Determine the neuroprotective efficacy of the optimal CpG ODN (K- and D-mix) and IMQ as prophylactic therapy in a model of cortical stroke in female NHPs. Aim 6. Determine pharmacokinetic and toxicity profiles of CpG ODN (K- and D-mix) and IMQ as potential stroke therapeutics. Aim 7. Submit an IND application for the optimal TLR candidate based on efficacy, pharmacokinetics and toxicity profiles. RELEVANCE: Many drug treatments to protect the brain from stroke have been tried and failed. This proposal offers a new approach based on the brain's own endogenous neuroprotective program. We will investigate 3 new drugs that have been shown to be safe in humans and test them as prophylaxis against ischemic brain injury. We will first test these drugs in a relevant primate model of stroke before moving to a clinical trial to treat humans that are at very high risk for future stroke.